An Efficient and Sustainable Synthesis of the Antimalarial Drug Tafenoquine

An 11-step, 8-pot synthesis of the antimalarial drug tafenoquine succinate was achieved in 42% overall yield using commercially available starting materials. Compared to the previous manufacturing processes that utilize environmentally egregious organic solvents and toxic reagents, the current route features a far greener (as measured by Sheldon’s E Factors) and likely more economically attractive sequence, potentially expanding the availability of this important drug worldwide.

S3 nm). The plates were further analyzed with the use of an aqueous ceric ammonium molybdate stain or ethanolic vanillin and developed with a heat gun. All commercially available reagents were used without further purification. Flash chromatography was performed using Silicycle Silicaflash® P60 unbonded grade silica.

HPLC:
HPLC analysis was performed on an Agilent 1220 series HPLC with an Agilent Poroshell HPH C18 column (4.6 x 50 mm, 2.7 μm). HPLC-grade solvents were obtained from Fischer Scientific. S4

General Procedure
3.1 Synthesis of p-acetoanisidine (5) Step 1a: Procedure: p-Anisidine 3 (2.46 g, 20 mmol), methyl acetoacetate 4a (13 mL, 6 equiv) and 2 wt % TPGS-750-M/H2O solution (40 mL) were added to a 100 mL RBF with a Teflon-coated magnetic stir bar. The reaction was stirred at 85 °C for 36 h (as monitored by TLC). After completion, the reaction was extracted with 2 x 25 mL of EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Purification was by flash chromatography using a hexane gradient  to afford the desired compound as a light grey solid as the major product 5, 41% (1.7 g), and as a yellow solid for the minor product 5a (37%; 1.63 g).

Synthesis of 6-methoxy-4-methyl-2-quinolone (6):
Procedure: To a 2 dr vial equipped with a PTFE-coated magnetic stir bar was added acylated compound 5 (1 equiv, 1 mmol, 207.2 mg) and 98% sulfuric acid (3 equiv, 3 mmol, 300.2 mg) at rt. The reaction was stirred at 95 °C for 3 h (as monitored by TLC). After cooling to rt, ice cold water was added to the reaction mixture and neutralized with NaHCO3 and the resulting precipitate was filtered to afford the desired compound 6 (166 mg, 88% yield, >99% purity by HPLC) as a brown solid.
The resulting precipitate was filtered, washed with water three times and dried under vacuum at rt to afford the desired compound 7 (90 mg, 87% yield).
Toluene recovery. The above reaction was performed on 10 mmol scale (1.89 g, 20 mL toluene added).
After completion, the reaction mixture was quenched by addition of 30% aqueous NH4OH. The resultant precipitate was filtered and toluene was separated from the aqueous layer using a separatory funnel. The crude organic layer was subsequently subjected to distillation to recover pure toluene (12.5 mL, 62.5%).
To the reaction mixture, water (0.5 mL) was added, and extracted with, EtOAc (3 x 3 mL), and the organic S12 layer was washed with 10% NaOH solution and then brine. The organic layer was dried over anhydrous MgSO4. The mixture was concentrated in vacuo to afford crude product as a black solid, which was then purified by silica gel flash column chromatography using hexanes / EtOAc (90:10) to afford pure product 12 (78 mg, 76% yield, 99.5% purity by HPLC) as a yellow solid.
Neat conditions (entry 9): In a 2-dram vial containing a PTFE-coated magnetic stir bar was added 3-(trifluoromethyl)phenol 11 (4 mmol, 2 equiv, 648.4 mg) and KOH as a powder (4 mmol, 2 equiv, 224.4 mg). The reaction mixture was heated to 75 °C and held at this temperature until all the KOH dissolved (ca. 15 min). Then, 5-chloro-2,6-dimethoxy-4-methyl-8-nitroquinoline 10 (1 equiv, 2 mmol, 565.4 mg) was added in one portion and the resulting mixture was stirred for 8 h at 75 °C. Upon completion, DI water (0.5 mL) was added and the resulting yellow precipitate was collected via centrifugation, washed with 1 M NaOH (2 x 0.5 mL) and water (2 x 0.5 mL) by repeated resuspension in water and centrifugation, then dried under vacuum at rt to afford the pure product 12 as a yellow solid (750.1 mg, 92%).
The reaction vial was closed and a septum was punctured with a needle (18 G) attached with a prefilled balloon of hydrogen gas. The headspace of the vial was replaced with H2 by unscrewing the cap under positive H2 flow for ca. 5 sec. Finally, the reaction mixture was stirred at rt for 18 h. After complete conversion of starting material, saturated NaHCO3 solution (50 uL) was added to the reaction which was then stirred briefly. The reaction mixture was filtered through a short plug of silica and washed with EtOAc.
Removal of the organic solvent led to crude product. Purification by flash chromatography using EtOAc / hexanes (0 to 30%) afforded 13 as a purple solid (88.5 mg, 94% yield).

Synthesis of tafenoquine succinate salt (2) via nitro group reduction
Scheme S6: Synthesis of tafenoquine succinate salt (2)  equiv, 307.9 mg) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one 4 (3.75 mmol, 1.5 equiv, 533 mg) after which the vial was sealed and allowed to stir at 95 °C for 8 h. Complete conversion of starting material was determined by TLC ((30:70 EtOAc:hexanes), ). To the same reaction mixture was then added 98% sulfuric acid (3 equiv, 7.5 mmol, 750 mg) at rt. The reaction was stirred at 95 °C for 3 h while the extent of conversion was monitored by TLC (50:50 EtOAc:hexanes). After cooling to rt, ca. 1 mL of ice cold water was added dropwise to the reaction mixture which was then neutralized by dropwise addition of saturated NaHCO3 and the resulting precipitate was filtered and dried under high vacuum for 16 h to afford the desired compound 6 (406.6 mg, 86% yield) as a brown solid.

2-
Step, 1-pot synthesis of intermediate 9 Scheme S8: 2-Step, 1-pot synthesis of intermediate 9 In a 1-dram vial containing a PTFE-coated magnetic stir bar was added 2-chloro-6-methoxy-4methylquinoline 7 (1 equiv, 0.5 mmol, 103.8 mg). Anhydrous NaOMe (5 equiv, 2.5 mmol, 135.1 mg) was then added to the vial in a glove box and the reaction vial was sealed with a rubber septum, removed from the glove box, to which was then added anhydrous MeOH (1 mL) via syringe. The reaction mixture was stirred at 70 o C for 24 h. After completion of the reaction as monitored by TLC (5:95 EtOAc:hexanes), the reaction mixture was cooled to rt, then AcOH (4 equiv, 2 mmol, 114 μL) was added to quench excess NaOMe and the mixture was stirred for 10 min, after which MeOH was removed in vacuo. To the crude residue was added AcOH (666 μL) followed by dropwise addition of a solution of SO2Cl2 (2 equiv, 1 mmol, 81 μL) in AcOH (222 μL) and the reaction was stirred at 60 °C for 0.5 h, then poured into ice water (ca. 20 mL). The resulting precipitate was collected by suction filtration, washed with cold water, and air dried to afford 9 as a white solid (105.3 mg, 89%).

Scheme S9: 3-Step tandem sequence to afford intermediate 15
In a 1-dram vial containing a PTFE-coated magnetic stir bar was added 3-(trifluoromethyl)phenol 11 (0.5 mmol, 2 equiv, 81.1 mg) and KOH powder (0.5 mmol, 2 equiv, 28.1 mg). The reaction mixture was heated to 75 °C and held at this temperature until all the KOH had dissolved (about 15 min). Then, 5-chloro-2,6dimethoxy-4-methyl-8-nitroquinoline 10 (0.25 mmol, 1.0 equiv, 71.7 mg) was added in one portion and the resulting solution was heated at this temperature for 8 h. After complete conversion of starting material as indicated by TLC (10:90 EtOAc:hexanes), the reaction mixture was cooled to rt and carbonyl iron powder (CIP; 1.25 mmol, 5.0 equiv, 69.8 mg) and NH4Cl (0.75 mmol, 3 equiv, 40.1 mg) were added. The vial was purged with argon, then 95% EtOH (0.5 mL) and conc. HCl (2 equiv, 42 ul) were added at rt, and the resulting mixture was allowed to stir at 55 °C until completion as monitored by TLC (10:90 EtOAc:hexanes). Saturated NaHCO3 solution (50 uL) was added to the reaction mixture which was stirred briefly, then EtOAc (~0.5 mL) was added to the vial and after brief stirring, the contents of the vial were filtered through ~1 cm of Celite in a pipette and rinsed with EtOAc (0.5 mL). The solvent was removed by rotary evaporation and the product concentrated under vacuum to provide crude product as a thick purple liquid which was used without further purification.
In a 1-dram vial with a PTFE-coated magnetic stir bar, the crude product from the previous step was used along with N-(4-oxopentyl)phthalimide 14 (0.375 mmol, 1.5 equiv, 86.7 mg) and 2-picolineborane (0.375 mmol, 1.5 equiv, 40.0 mg). Glacial acetic acid (0.5 mL) was then added, and the reaction was stirred at rt S19 for 16 h, then evaporated to dryness in vacuo. The resulting product was purified by silica gel flash column chromatography using EtOAc: hexanes (3:1) to afford the desired compound 15 in 89% yield (132.5 mg) as a yellow solid.

3-
Step tandem sequence to afford intermediate 17 (Route 2) Scheme S10: 3-Step tandem sequence to afford intermediate 17 In a 1-dram vial containing a PTFE-coated magnetic stir bar was added 3-(trifluoromethyl)phenol 11 (0.5 mmol, 2 equiv, 81.1 mg) and KOH powder (0.5 mmol, 2 equiv, 28.1 mg). The reaction mixture was heated to 75 °C and held at this temperature until all the KOH was dissolved (about 15 min). Then, 5-chloro-2,6dimethoxy-4-methyl-8-nitroquinoline 10 (0.25 mmol, 1.0 equiv, 71.7 mg) was added in one portion and the resulting solution was kept at this temperature for 8 h. After complete conversion of starting material as indicated by TLC (10:90 EtOAc:hexanes), the reaction mixture was cooled to rt and carbonyl iron powder (CIP; 1.25 mmol, 5.0 equiv, 69.8 mg) and NH4Cl (0.75 mmol, 3 equiv, 40.1 mg) was added. The vial was purged with argon, then 95% EtOH (0.5 mL) and HCl (2 equiv, 42 uL) were added at rt, and the resulting mixture was allowed to stir at 55 °C until completion as monitored by TLC (10:90 EtOAc:hexanes). The EtOH was evaporated under reduced pressure then saturated NaHCO3 solution (200 μL) and EtOAc (~0.5 mL) were added to the vial which was further stirred briefly, after which the contents of the vial were filtered through ~1 cm of Celite in a pipette and rinsed with EtOAc (0.5 mL). The solvent was removed by rotary evaporation and the product concentrated under vacuum to provide crude product as a thick purple liquid which was used without further purification.
In a 1-dram vial with a PTFE-coated magnetic stir bar, the crude product from the previous step was used along with 5-nitro-2-pentanone 16 (0.37 mmol, 1.4 equiv, 49.2 mg) and 2-picolineborane (0.3 mmol, 1.2 equiv, 32.2 mg). Glacial acetic acid (0.5 mL) was then added, and the reaction was stirred at rt for 5 h and evaporated to dryness in vacuo. The obtained the brown oily residue dissolved in ethanol (0.2 mL). The solution was cooled to 5 °C for 24 h. The resulted crystals were filtered off, washed with cold ethanol (0.1 ml) and dried in vacuo at rt for 3-4 h to afford the desired compound 17 (113.8 mg, 92% yield) as a yellow solid.

Complete E Factor (cEF) calculations
To compare the present process with the conventional one, the complete E Factor (cEF) was used according to its definition by Roschangar et al. 10 Masses of waste and products are those form the protocols described in the SI section 5.4. Masses were normalized to 1 mmol of starting material for the first pot, then subsequent pots were adjusted down in scale based on the yields of the preceding pots.